Headache in Epilepsy: Prevalence and Clinical Features

Mainieri et al. The Journal of Headache and Pain (2015) 16:72 DOI 10.1186/s10194-015-0556-y

RESEARCH ARTICLE Open Access Headache in epilepsy: prevalence and clinical features G Mainieri1,2, S Cevoli1, G Giannini1,2, L Zummo1,2,3, C Leta1,2, M Broli1,2, L Ferri1,2, M Santucci1,2, A Posar1,2, P Avoni1,2, P Cortelli1,2, P Tinuper1,2 and Francesca Bisulli1,2*

Abstract Background: Headache and epilepsy are two relatively common neurological disorders and their relationship is still a matter of debate. Our aim was to estimate the prevalence and clinical features of inter-ictal (inter-IH) and peri-ictal headache (peri-IH) in patients with epilepsy. Methods: All patients aged ≥ 17 years referring to our tertiary Epilepsy Centre were consecutively recruited from March to May 2011 and from March to July 2012. They underwent a semi-structured interview including the International Classification Headache Disorders (ICHD-II) criteria to diagnose the lifetime occurrence of headache.χ2-test, t-test and Mann–Whitney test were used to compare clinical variables in patients with and without inter-IH and peri-IH. Results: Out of 388 enrolled patients 48.5 % had inter-IH: migraine in 26.3 %, tension-type headache (TTH) in 19.1 %, other primary headaches in 3.1 %. Peri-IH was observed in 23.7 %: pre-ictally in 6.7 %, ictally in 0.8 % and post-ictally in 19.1 %. Comparing patients with inter-ictal migraine (102), inter-ictal TTH (74) and without inter-IH (200), we found that pre-ictal headache (pre-IH) was significantly represented only in migraineurs (OR 3.54, 95 % CI 1.88-6.66, P < 0.001). Post-ictal headache (post-IH) was significantly associated with both migraineurs (OR 2.60, 95 % CI 1.85-3.64, P < 0.001) and TTH patients (OR 2.05, 95 % CI 1.41-2.98, P < 0.001). Moreover, post-IH was significantly associated with antiepileptic polytherapy (P < 0.001), high seizure frequency (P = 0.002) and tonic-clonic seizures (P = 0.043). Conclusions: Migraine was the most represented type of headache in patients with epilepsy. Migraineurs are more prone to develop pre-IH, while patients with any inter-IH (migraine or TTH) are predisposed to manifest a post-IH after seizures. Keywords: Headache; Epilepsy; Migraine; Pre-ictal headache; Post-ictal headache

Background and therapeutic overlap [2]. Studies on the association be- Epilepsy and primary headache disorders affect individ- tween epilepsy and other types of primary headache are uals of all ages worldwide. Several studies have been difficult to perform as tension-type headache (TTH) is ex- performed to attest if there is a relationship between tremely common in the general population [3] whereas the two conditions, in order to verify the existence of a cluster headache is very rare [4]. For this reason most causal association or if the two disorders can occur in studies analyzing the prevalence of headache in patients the same individual by chance. In the last century with epilepsy focused only on migraine and results remain Gowers first advanced the clinical hypothesis of a relation- controversial (Table 1) [5–21]. ship between epilepsy and migraine [1] since the two con- According to its temporal relationship with epileptic sei- ditions show a well-recognized clinical, pathophysiological zures, headache can be classified as inter-ictal (inter-IH) or peri-ictal (peri-IH). Inter-IH is not temporally related * Correspondence: [email protected] to seizures, whereas peri-IH manifests in their time frame 1IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, (pre-ictally, ictally, post-ictally) [7, 8]. Literature data on Bologna, Italy 2Department of Biomedical and Neuromotor Sciences, University of Bologna, the relation between inter-IH (in particular migraine) and Bellaria Hospital, Via Altura, 3 – 40139, Bologna, Italy peri-IH are controversial owing to the methodological Full list of author information is available at the end of the article

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Table 1 Literature prevalence of migraine in patients with epilepsy Authors Sample M/F Age Methods Results N of pts yrs Migraine Schon and Blau 1987 [5] 100 39/61 32 mean Interview 9 % Ottman and Lipton 1994 [6] 1948 40 %/ ≥18 Structured telephone interviews + medical 24 % 60 % records review for 60 % of probands Ito and Shachter 1996 [7] 162 82/80 19-65 range Questionnaires mailed to the subjects + medical NAa records review Ito et al. 1999 [8] 109 36/73 38 ± 12 meanb Questionnaire + interview + medical records review 12.8 % Velioglu and Ozmenoglu 1999[9] 412 212/200 15-70 range Interview with a standardized questionnaire 14 % Leniger et al. 2001 [10] 341 154/187 40 ± 15 mean Interview with a standardized questionnaire 18.2 % Karaali Savrun et al. 135 80/55 ≥10 Questionnaire administered to patients 14.8 % 2002 [11] Förderreuther et al. 2002 [12] 110 69/41 35.2 mean Semi-standardized interview 10 %b Ito et al. 2004 [13] 364 163/201 12-81 range Structured interview with standardized questionnaire 8 % Syvertsen et al. 2007 [14] 109 44/65 20-71 range Questionnaire + semi-structured telephonic interview 20 % Kwan et al. 2008 [15] 227 98/129 36.0 ± 11.3 mean Interview with standardized questionnaire + seizures 6.6 %b and headache diary over the 3-month observation period + final interview HELP Study Group 2010 [16] 597 348/249 ≥13 Questionnaire at initial visit 12.4 % Tonini et al. 2012 [17] 492c 154/338 ≥18 Direct interview with questionnaire 18.3 %b Duchaczek et al. 2012 [18] 201 106/95 ≥18 Semi-structured interview 11 % Winawer et al. 2013 [19] 730d 285/445 ≥12 Telephone or in-person interview + medical 25.2 %e record abstraction Gameleira et al. 2013 [20] 304 141/163 4-88 range Patients evaluated at the epilepsy clinic 32.9 %f Wang et al. 2014 [21] 1109 607/502 ≥18 Self-administered questionnaire + standardized 12.53 % semi-structured telephone interview N, number; pts, patients; M, males; F, females; yrs, years; NA, not available aa prevalence of inter-ictal migraine is not clearly identifiable; the authors report a prevalence of inter-ictal headache in 64 % of patients, approximately a half of them with a pounding quality and almost 70 % of them often accompanied by nausea and/or vomiting, photophobia or phonophobia bcalculated by the authors cthis multicenter study involved 1167 patients from epilepsy and headache centers, we considered only patients with epilepsy d371 probands, 231 siblings, 128 parents: all with epilepsy; e23.5 % probands, 22.5 % siblings, 35.2 % parents fthe authors of the study does not distinguish between inter-ictal migraine and post-ictal headache with migrainous features

heterogeneity of previous studies [5–21]. Moreover, in the Study design and participants context of seizure-related headaches, entities identified as This is a cross-sectional study conducted at the out- “migralepsy” or “epileptic headache” are still matter of dis- patient clinic of our tertiary Epilepsy Center between cussion [22]. March and May 2011 and March and July 2012. Patients The aim of this study was to estimate the prevalence aged ≥ 17 years were consecutively asked to participate of headache in adult patients with epilepsy, describing in the study and a self-report form was administered to its clinical features and temporal relationship with seiz- those who accepted. This form dichotomously ruled out ure occurrence. patients who reported a lifetime presence of headache and patients who had never suffered from headache. If patients confirmed the occurrence of headache, trained Methods physicians (GM, CL, LF), blinded to the patient’s diagno- The institutional review board of the IRCCS Institute of sis, conducted a semi-structured interview characterizing Neurological Sciences of Bologna approved the project. the type of inter-IH and peri-IH, if present. Headache Clinical investigations have been carried out in accord- data were revised by headache experts (SC, GG, PC), ance with the Helsinki Declaration adopted by the 18th who validated the diagnosis according to ICHD-II cri- World Medical Assembly in Helsinki, in 1964, as last teria [23]. Expert epileptologists (FB, PT, PA, MS) clas- amended by the World Medical Assembly. sified epileptic seizures and syndromes according to Mainieri et al. The Journal of Headache and Pain (2015) 16:72 Page 3 of 10

the 2010 International League Against Epilepsy (ILAE) generalized seizure and resolves within 72 h after the seiz- Commission report [24]. ure” [23]. We collected data on the lifelong presence of All patients with a diagnosis of epilepsy were in- headache and verified if headache attacks had occurred in cluded in the study. We excluded patients who had ar- the three months prior to the interview. We defined as rived for a first visit and proved not to be affected by “inter-ictal headache” all headaches that manifested within epilepsy (i.e. psychogenic non-epileptic seizures, sleep a time period of the epileptic disease and whose attacks disorders, syncope, dystonia), patients with a doubtful were not temporally related to an epileptic seizure. epilepsy diagnosis, patients who had only a single seiz- According to ICHD-II criteria [23], inter-IH was divided ure, and patients with a severe mental retardation. into migraine (with or without aura), probable migraine, TTH, probable TTH, cluster headache, and other primary headaches. Secondary headaches in structural epilepsies Data collection were ruled out by means of imaging studies and were not The self-report form administered contained socio- considered in our analyses. demographic data and a preliminary question regarding the lifetime presence of headache. Patients who an- Statistical analysis swered affirmatively also had to indicate their age at Clinical variables in patients with inter-ictal migraine, headache onset, headache in the previous three months, inter-ictal TTH and without inter-IH were analyzed. In the frequency of attacks and the use of analgesics in a addition we compared clinical features between patients month. On the same form, patients who reported head- with post-IH and those without post-IH and between ache also answered the already validated ID migraine, a patients with pre-IH and those without pre-IH. We per- three-item instrument for migraine screening, and then formed χ2-test and t-test to compare categorical vari- underwent an ad hoc semi-structured interview with ables. T-test and Mann–Whitney test were performed to trained physicians concerning inter-IH and peri-IH. The evaluate continuous variables with a symmetrical and formulation of this semi-structured interview was the asymmetrical distribution respectively. A logistic regres- product of a collaboration between the Epilepsy and sion model was used to calculate OR and a 95 % confi- Headache Centers. The clinical data collected to evaluate dence interval CI to assess the association between inter-IH concerned headache in other family members, dependent and independent variables. Adjustment for age at headache onset, lateralization of headache, quality the possible effect of confounding variables such as age, of pain, duration, intensity, frequency in a month, wors- sex and migraine prophylactic therapy when appropriate ening with physical activity, use of analgesic treatment, was performed through a multivariable-adjusted logistic associated symptoms like photophobia, phonophobia, regression analysis. Statistical significance was set at p nausea, vomiting, and presence of aura. For patients value < 0.05. Statistical analyses were performed with who presented peri-IH, the interview also included ques- STATA® version 12.0. tions on timing of onset (pre-ictal, ictal or post-ictal headaches), duration, and features of peri-IH. Finally ex- Results pert epileptologists filled out the last section of the form Study population reviewing patients’ clinical records and collecting data The flow diagram of the study is illustrated in Fig. 1 and on epilepsy syndrome, seizure types, frequency of sei- the main features of the population in Table 2. Out of the zures, epilepsy etiology, age at epilepsy onset, disease original pool of 446 outpatients attending the Epilepsy duration, current antiepileptic medications, and photo- Center we included in the study 388 cases (209 female, sensitivity. The interview had previously been tested on 53.9 %) with a confirmed diagnosis of epilepsy. The mean a series of 50 consecutively recruited patients with epi- age of patients at the interview was 41.25 ± 15.70 years lepsy, showing that the diagnosis gathered from the (median 39, range 17–84). One hundred and one patients semi-structured interview correlated with that of the had generalized epilepsy (26.0 %), 77 with a genetic eti- headache experts. ology and 24 with a structural/metabolic or unknown etiology. Two hundred and eighty patients had focal epilepsy Definitions and classifications (72.2 %), four with a genetic etiology and 276 with a struc- According to the temporal relationship with seizures, tural/metabolic or unknown etiology. Seven patients had peri-IH was divided into pre-ictal headache (pre-IH), ictal unclassified epilepsy (1.8 %). The median age at epilepsy and post-ictal headache (post-IH). Pre-IH was defined as onset was 15 years (interquartile range 8–23.5) and the appearing within 24 h before the seizure [18, 22, 25]. Ictal median epilepsy duration at the interview was 20.5 years headache was present exclusively during the seizure [22]. (interquartile range 11–32). One hundred and thirty-four Post-IH was defined according to the ICHD-II as a “head- patients (34.5 %) had sporadic seizures (few episodes per ache which develops within 3 h following a partial or year), 132 (34.0 %) had been seizure-free for at least two Mainieri et al. The Journal of Headache and Pain (2015) 16:72 Page 4 of 10

Fig. 1 Flow diagram of enrolled patients. Patients recruited from a pool of 454 subjects referred to the Bologna Epilepsy Center. Thirty-six patients excluded after medical review of their clinical records that did not confirm a diagnosis of epilepsy years at the interview while 119 (30.7 %) had monthly/ 1. Pre-ictal headache present in 26 patients (6.7 %), daily or multidaily seizures (in three cases frequency could with migrainous features in 16, with tension-type not be assessed). One hundred and eighty-five patients quality in five, other in five. Only in one of these (47.7 %) were taking antiepileptic monotherapy, 188 patients did the attacks disclose the features of (48.4 %) received polytherapy (≥2 AEDs), and 15 (3.9 %) migraine with aura but did not present a strict had no therapy at the interview. In the latter group ther- temporal relationship (within one hour) with seizure apy had been withdrawn in 13 cases 4.5 years on average onset. Nineteen patients (4.9 %) with pre-IH had before the interview, after many years of seizure freedom also inter-ictal migraine (one with aura) while one one patient had a recent disease history with only two sei- had an unclassified headache. In most of these cases zures and was not on any therapy at the interview while (16/20), pre-IH had migrainous features similar in another had sporadic seizures and was not on therapy of quality to the habitual headache attack, whereas four his own accord. patients were not able to characterize the features of their pre-IH. Another three patients (0.8 %) present- Headache ing pre-IH had an inter-ictal TTH that showed simi- Overall 209 patients (53.9 %) reported a lifetime occur- lar quality features to the habitual attacks in all rence of headache: 188 had inter-IH (48.4 %), while peri- cases. Three patients (0.8 %) not complaining of IH occurred in 92 patients (23.7 %). Among them 71 inter-IH only presented headache before seizures: it patients (18.3 %) had an associated inter-IH, while 21 showed tension-type headache-like features in two (5.4 %) only had headache related to the seizures (Fig. 2). patients, while one patient did not recall the features The latter occurred before the seizure in three patients, of his pre-IH. during the seizure in another three cases and in the 2. Ictal headache in three cases (0.8 %), none of whom post-ictal period in 16 patients (one of them had an ictal had an inter-IH. The first patient had a myoclonic headache which continued post-ictally). Out of the 188 epilepsy and referred a sense of head pressure lasting patients with inter-IH, 35 (18.6 %) did not report head- a few seconds, involving the whole head, in corres- aches in the previous three months. According to pondence with myoclonic jerks. The second patient ICHD-II criteria [23], patients with inter-IH were classi- had a focal epilepsy of temporal origin of the right fied as follows: 102 patients had migraine (26.3 %), in- hemisphere and referred a very intense mostly cluding six with aura (1.5 %) and 16 with probable frontal throbbing pain (undetermined side) a few migraine (4.1 %), 74 had TTH (19.1 %), including two seconds before the seizure. The third patient had a with probable TTH (0.5 %), two patients had cluster focal epilepsy of temporal origin of the left hemisphere headache (0.5 %), one patient had primary stabbing and reported a headache starting during the seizure headache (0.03 %) and nine patients had unclassified and often continuing in a post-IH. The headache headache (2.3 %). showed a tightening quality of moderate to severe According to its temporal relationship with seizure on- intensity not associated with autonomic symptoms, set peri-ictal headache was distinguished as: photophobia or phonophobia. Mainieri et al. The Journal of Headache and Pain (2015) 16:72 Page 5 of 10

Table 2 Clinical features of the study population Total Males Females Sample 388 179 (46.13) 209 (53.87) Age (mean ± SD) 41.25 ± 15.70 41.92 ± 16.32 40.68 ± 15.15 Age at epilepsy onset 15; 8–23.5 16; 7-26 14; 9-22 (med; p25-p75) Epilepsy duration 20.5; 11-32 20; 10-31 21; 11-32 (med; p25-p75) Epilepsy Generalized 101 (26.03) 46 (25.70) 55 (26.32) Focal 280 (72.16) 129 (72.07) 151 (72.25) Unclassified 7 (1.80) 4 (2.23) 3 (1.43) Frequency of seizures at observation Sporadic 134 (34.54) 59 (32.96) 75 (35.89) Monthly/daily 119 (30.67) 49 (27.37) 70 (33.49) Seizure-free 132 (34.02) 69 (38.55) 63 (30.14) AED therapy Monotherapy 185 (47.68) 91 (50.84) 94 (44.98) Fig. 2 Flow chart describing patients presenting headache. This Polytherapy 188 (48.45) 82 (45.81) 106 (50.72) subgroup is further divided into patients with inter-ictal headache No therapy 15 (3.87) 6 (3.35) 9 (4.31) and patients with peri-ictal headache, with an overlapping group of individuals who presented both conditions. Inter-IH, inter-ictal headache; Photosensitivity 23 (5.93) 10 (5.59) 13 (6.22) Peri-IH, peri-ictal headache Inter-IH 188 (48.45) 68 (37.99) 120 (57.42) Migraine without aura 80 (20.62) 25 (13.97) 55 (26.32) them and TTH-like features in eight (8/16), whereas Migraine with aura 6 (1.55) 4 (2.23) 2 (0.96) it could not be better characterized in the remaining Probable migraine 16 (4.12) 5 (2.79) 11 (5.26) four cases. TTH 72 (18.56) 27 (15.08) 45 (21.53) Probable TTH 2 (0.52) 1 (0.56) 1 (0.48) Migraineurs vs TTH vs patients without inter-IH We compared clinical features in patients with inter- Cluster headache 2 (0.52) 0 (0.00) 2 (0.96) ictal migraine, patients with inter-ictal TTH and patients Peri-IH 92 (23.71) 34 (18.99) 58 (27.75) who did not have any inter-IH (Table 3). Female sex was Pre-ictal headache 26 (6.70) 6 (3.35) 20 (9.57) prevalent both in the migraineurs group (P < 0.001) and Ictal headache 3 (0.77) 0 (0.00) 3 (1.44) in the TTH group (P = 0.009), compared to patients Post-ictal headache 74 (19.07) 30 (16.76) 44 (21.05) without inter-IH. Migraineurs had a lower mean age N, number; SD, standard deviation; med, median; p25-p75, 25th and 75th than patients without inter-IH (P = 0.013). There were percentile; AED, anti-epileptic drug; Inter-IH, inter-ictal headache; TTH, tension- no significant differences in epilepsy syndrome, seizure type headache; Peri-IH, peri-ictal headache. Figures given as N (%), unless frequency, therapy or photosensitivity among the three otherwise stated groups. After adjustment for age, sex and therapy, both 3. Post-ictal headache occurring in 74 patients (19.1 %) groups of patients with inter-ictal migraine (OR 2.68, with the following features: migraine quality in 37, 95 % CI 1.96-3.64, P < 0.001) and TTH (OR 1.87, 95 % TTH-like in 30, other in seven. Thirty-eight patients CI 1.33-2.63, P < 0.001) were significantly associated with (9.8 %) had an associated inter-ictal migraine (no the occurrence of peri-IH. Pre-IH was significantly asso- patients with aura). Their post-IH in most cases ciated only with patients with inter-ictal migraine, both (31/38) had migrainous features, in six cases it was compared to patients without inter-IH (OR 3.54, 95 % described as TTH-like, while one patient did not CI 1.88-6.66, P < 0.001) and to patients with TTH (OR recall the features of his post-IH. Twenty patients 5.29, 95 % CI 1.50-18.68, P = 0.010). Post-IH occurred (5.1 %) had an inter-ictal TTH. Their post-IH significantly in both groups of migraineurs (OR 2.60, showed similar TTH-like features in 16 (16/20) 95 % CI 1.85-3.64, P < 0.001) and TTH patients (OR patients and migrainous features in two (2/20), 2.09, 95 % CI 1.44-3.03, P < 0.001) compared with while in two patients it was unclassified. Sixteen patients without inter-IH, while there was no statistical patients (4.1 %) manifested headache only after difference between them (OR 1.69, 95 % CI 0.86-3.31, seizures with migrainous features in four (4/16) of P = 0.127). Mainieri et al. The Journal of Headache and Pain (2015) 16:72 Page 6 of 10

Table 3 Comparison of clinical features between subgroups of patients with inter-ictal migraine, inter-ictal tension-type headache and patients without inter-ictal headache Inter-ictal Migraine Inter-ictal TTH No inter-IH p value OR (CI 95 %) Group Comparison (Group 1) (Group 2) (Group 3) Sample 102 (26.29) 74 (19.07) 200 (51.55) Males 34 (23.45) 28 (20.14) 111 (79.86) <0.001; - 1 vs 3; Females 68 (43.31) 46 (34.07) 89 (65.93) 0.009 2 vs 3 Age (mean ± SD) 38.57 ± 13.73 40.34 ± 16.46 43.26 ± 16.27 0.013 - 1 vs 3 Age at epilepsy onset (med; p25-p75) 15; 10-21 15; 10-26 15; 6-25 0.877 - - Epilepsy duration (med; p25-p75) 19; 9-31 19; 10-28 21.5; 12-34 0.076 - - Epilepsy Generalized 27 (26.47) 19 (25.68) 51 (25.50) 0.855 - - Focal 73 (71.57) 55 (74.32) 144 (72.00) 0.937 - - Unclassified 2 (1.96) 0 (0.00) 5 (2.50) 0.768 - - Frequency of seizures at observation Sporadic 37 (36.27) 24 (32.43) 67 (33.50) 0.631 - - Monthly/daily 30 (29.41) 24 (32.43) 62 (31.00) 0.777 - - Seizure-free 34 (33.33) 26 (35.14) 69 (34.50) 0.840 - - Tonic-clonic seizures 73 (71.57) 48 (64.86) 113 (56.50) 0.011 1.39 (1.08 - 1.80) 1 vs 3 AED therapy Monotherapy 54 (52.94) 36 (48.65) 91 (45.50) 0.221 1.16 (0.91 - 1.47) - Polytherapy 43 (42.16) 37 (50.00) 101 (50.50) 0.170 0.85 (0.67 - 1.08) - No therapy 5 (4.90) 1 (1.35) 8 (4.00) 0.715 1.11 (0.63 - 1.97) - Photosensitivity 8 (7.84) 4 (5.41) 11 (5.50) 0.428 - - Peri-ictal headache 48 (47.06) 22 (29.73) 21 (10.50) 0.019a; 2.18 (1.14 - 4.19); 1 vs 2; <0.001a; 2.68 (1.96 - 3.64); 1 vs 3; <0.001b; 1.87 (1.33 - 2.63) 2 vs 3; Pre-ictal headache 19 (18.63) 3 (4.05) 3 (1.50) 0.010a; 5.29 (1.50 - 18.68); 1 vs 2;

<0.001a 3.54 (1.88 - 6.66) 1 vs 3 Ictal headache 0 (0.00) 0 (0.00) 3 (1.50) 0.214 - - Post-ictal headache 38 (37.25) 20 (27.03) 16 (8.00) <0.001a; 2.60 (1.85 - 3.64); 1 vs 3; <0.001b; 2.09 (1.44 - 3.03); 2 vs 3; 0.127b 1.69 (0.86 - 3.31) 1 vs 2 N,number;TTH,tension-typeheadache;inter-IH,inter-ictal headache; OR, odds ratio; CI, confidence interval; vs, versus; SD, standard deviation; med, median; p25-p75, 25th and 75th percentile; AED, anti-epileptic drug aMultivariable model adjusted for age, sex and anti-migraine therapy bMultivariable model adjusted for age and sex Figures given as N (%), unless otherwise stated

Patients with pre-IH vs patients without pre-IH and seizure-free at the interview (P = 0.012) was signifi- patients with post-IH vs patients without post-IH cantly higher. We compared patients with and without pre-IH and patients with and without post-IH (Table 4). Pre-IH Discussion was significantly associated with female sex (P = 0.015). Headache is a significantly frequent symptom both in Variables significantly associated with post-IH were patients with epilepsy and in the general population. AEDs polytherapy (P < 0.001), high frequency of sei- This is why the prevalence of primary headaches in adult zures (P = 0.002), and tonic-clonic seizures (P = 0.041). patients with epilepsy remains a matter of debate. Differ- Conversely the proportion of patients without post-IH ences in target populations, age range, data collection, with an AED monotherapy (P=0.002) and who were diagnostic and classification criteria, methodological Mainieri et al. The Journal of Headache and Pain (2015) 16:72 Page 7 of 10

Table 4 Comparison of clinical features between patients with and without post-ictal headache and patients with and without pre-ictal headache Post-IH No Post-IH p value OR (CI 95 %) Pre-IH No Pre-IH p value OR (CI 95 %) Sample 74 (19.07) 314 (80.93) 26 (6.70) 362 (93.30) Males 30 (16.76) 149 (83.24) 0.283 - 6 (3.35) 173 (96.65) 0.015 - Females 44 (21.05) 165 (78.95) 20 (9.57) 189 (90.43) Age (mean ± SD) 38.08 ± 13.50 42.00 ± 16.10 0.053 - 38.08 ± 14.54 41.48 ± 15.77 0.286 - Age at epilepsy onset 12; 8-20 15; 8-24 0.135 - 13; 6 - 24 15; 8 - 23 0.601 - (med; p25-p75) Epilepsy duration (med; p25-p75) 21; 12-29 20; 11-32 0.879 - 20.5; 9-32 20.5; 11-32 0.529 - Epilepsy Generalized 18 (24.32) 83 (26.43) 0.710 - 2 (7.69) 99 (27.35) 0.027 - Focal 55 (74.32) 225 (71.66) 0.645 - 21 (80.77) 259 (71.55) 0.311 - Unclassified 1 (1.35) 6 (1.91) 0.745 - 3 (11.54) 4 (1.10) <0.001 - Frequency of seizures at observation Sporadic 23 (31.08) 111 (35.35) 0.487 - 10 (38.46) 124 (34.25) 0.663 - Monthly/daily 34 (45.95) 85 (27.07) 0.002 - 11 (42.31) 108 (29.83) 0.183 - Seizure-free 16 (21.62) 116 (36.94) 0.012 - 4 (15.38) 128 (35.36) 0.038 - Tonic-clonic seizures 53 (71.62) 185 (58.92) 0.041a 1.79 (1.02 - 3.12) 16 (61.54) 222 (61.33) 0.983 - AED therapy Monotherapy 23 (31.08) 162 (51.59) 0.002a 0.43 (0.25 - 0.74) 13 (50.00) 172 (47.51) 0.806 1.11 (0.50 - 2.45) Polytherapy 50 (67.57) 138 (43.95) <0.001a 2.64 (1.54 - 4.52) 13 (50.00) 175 (48.34) 0.870 1.07 (0.48 - 2.37) No therapy 1 (1.35) 14 (4.46) 0.219a 0.28 (0.04 - 2.15) 0 (0.00) 15 (4.14) 0.290 - Photosensitivity 5 (6.76) 18 (5.73) 0.737 - 1 (3.85) 22 (6.08) 0.642 - Inter-ictal headache 58 (78.38) 130 (41.40) <0.001 - 23 (88.46) 165 (45.58) <0.001 - Migraine 38 (51.35) 64 (20.38) <0.001b 4.06 (2.35 - 7.02) 19 (73.08) 83 (22.93) <0.001b 7.96 (3.20 - 19.80) Migraine without aura 38 (51.35) 58 (18.47) <0.001 - 18 (69.23) 78 (21.55) <0.001 - Migraine with aura 0 (0.00) 6 (1.91) 0.231 - 1 (3.85) 5 (1.38) 0.325 - TTH 20 (27.03) 54 (17.20) 0.053 - 3 (11.54) 71 (19.61) 0.311 - Post-IH, post-ictal headache; Pre-IH, pre-ictal headache; N, number; SD, standard deviation; med, median; p25-p75, 25th and 75th percentile; AED, anti-epileptic drug; TTH, tension-type headache aMultivariable model adjusted for age and sex bMultivariable model adjusted for age, sex and anti-migraine therapy Figures given as N (%), unless otherwise stated study design, and a lower reliability of retrospective stud- twofold higher risk for migraine in patients with epilepsy ies, may account for such controversial results. Moreover compared to their first degree relatives without epilepsy, most previous reports focused only on migraine, excluding and they also showed a nearly twofold risk of migraine the other types of primary headache (Table 1) [5–21]. compared to controls (24 % vs 12 %). However, data The close collaboration between the Epilepsy and from Brodtkorb et al. in a Norwegian population of epi- Headache Centers in our study allowed an accurate lepsy patients failed to confirm a statistically significant diagnosis of both epilepsy syndromes and primary association between migraine and epilepsy [6, 26]. headaches. Unlike the incidence of migraine we reported TTH in Among our patients migraine was the most frequent only 19 % of our cases, a lower prevalence compared to type of headache occurring in 26 % of patients, in ac- the general population. To date few studies have ad- cordance with previous studies in which the prevalence dressed TTH and epilepsy and no hypotheses on the re- of migraine ranged from 9 % to 30 %. Although the asso- lation between the two diseases have been put forward. ciation between these two diseases has been reported in We could speculate that our result is in line with the several epidemiologic studies their relationship has not type of headache. As a mild condition in spite of seizure been clarified yet [5–21]. Previous Ottman and Lipton’s disorder, TTH could be underestimated in patients with studies on 1948 patients with epilepsy demonstrated a epilepsy [11, 12, 14, 17, 18, 20, 21]. Mainieri et al. The Journal of Headache and Pain (2015) 16:72 Page 8 of 10

In any case it is interesting that in our cases both pa- considered. First of all most studies are retrospective tients with migraine and tension-type inter-IH reported [13, 14, 16, 25] and the few prospective studies avail- seizure-related headache with features similar in quality able were conducted either for a brief period [15] or to their habitual headache attacks. on pediatric populations [31, 32]. Moreover post-IH Analyzing accurately each different types of headaches prevalence could be influenced by the type and inten- in relation to seizures (peri-IH), we found a slightly sity of epilepsy, with a higher prevalence in samples of lower lifelong prevalence of headaches temporally re- patients with drug-resistant epilepsy [12, 30]. In our lated to seizures than in the literature (23 % vs 28-50 %) population post-IH was more frequently reported in [18]. We actually think it is probably due to the well- patients on polytherapy, suggesting a severe epilepsy controlled epilepsy in most of our patients, with only phenotype, and in patients with a higher seizure fre- very rare seizures, or no seizures at all. quency (monthly/daily) suggesting that the seizures act Pre-IH, usually with migrainous features, was reported as a trigger for headache attacks, as reported in litera- in 6 % of our population and only in patients with interic- ture [18, 29]. tal migraine, in line with previous studies [14, 16, 18, 21, Our study has some limitations. Firstly the retrospect- 25]. Only one of our patients with pre-IH had a migraine ive assessment of headaches can lead to a recall bias, es- with aura. In this case the headache attack started about pecially for peri-IH in patients who had their last seizure five hours before epileptic seizure onset, and hence did years before the interview. For this reason the prevalence not fall within the diagnostic criteria for “migralepsy” that of both pre-IH and post-IH may be underestimated in anyway is still a controversial entity [22]. the current study. Secondly we recruited patients from a Ictal headache occurred only in three patients (0.8 %) tertiary care center, thus there is a possible selection without inter-ictal headache. Two of them have temporal bias. However the features of our sample resemble those lobe epilepsy and the other one a myoclonic epilepsy. of population-based epidemiological studies on epilepsy All of them reported a tightening quality of headache [33]. This is mainly due to the fact that patients with se- with a sense of head pressure and throbbing pain during vere encephalopathies were excluded, and the catchment the seizure or a few seconds before. However, as an ictal area of our Institute comprised the entire city of Bologna EEG recording was lacking in these cases, a definition of and its hinterland, thus resembling a population. Finally “Epileptic Headache” was not corrected [9, 12, 27]. the absence of a control group limits the significance of There is considerable confusion regarding the definition our results. of “Epileptic Headache”, in both headache and epilepsy Over the last decade, possible pathogenetic mechanisms classifications (ICHD-II and ILAE). The ICHD-II classi- common to epilepsy and migraine have been investigated fication (2004) defines “Epileptic Headache” as a head- in depth. The two disorders seem to be genetically inter- ache with migraine features while the patient also has a related and are comorbid in several clinical syndromes focal epileptic seizure. These cases are extremely rare, [34]. An altered membrane channel function and an im- and the term is not used in the current ILAE and ICHD balance between excitatory and inhibitory factors seem to classification [23, 24]. In our study we found that a lower have a central role in the pathogenesis of the two disor- number of adults have ictal headache (recognized as a ders [28, 35–37]. Cortical spreading depression (CSD) is headache lasting from seconds to days, with evidence of believed to underlie migraine with aura attacks and, ac- ictal epileptiform EEG discharges) than children. We cording to some evidence, also migraine without aura can speculate that it is strictly due to different symptom- [28]. Our study disclosed a relatively low occurrence of atology that children have both in epilepsy and in head- migraine with aura (1.5 %) that seems not to support this ache. Children are in fact more likely to have autonomic hypothesis. It is likely that both CSD and other mecha- symptomatology attacks, with long-lasting ictal auto- nisms, such as different environmental or individual fac- nomic manifestations, while adults often have other sen- tors (genetic or otherwise), are implicated in the link sory or motor ictal signs. Thus, it is more probable that between migraine and epilepsy. many cases are genuine seizures imitating migraine, eas- By lowering the trigger threshold in the epileptic ily recognizable by an EEG recording [28]. focus, CSD could increase the risk of seizures, explain- At last in our study post-IH was the most frequent ing the onset of pre-IH [2]. Similarly, recurrent seizures type of peri-IH, occurring in 19 % of our patients: 37/ maypredisposeapatienttoCSD,inducingpost-IH 74 patients reported a migraine type, 30/74 a TTH, [37]. We suggest that, in analogy with migraine pa- and only in seven cases the quality of headache was tients, the stressful event represented by an epileptic unclassified. It is not straightforward to compare our seizure is a trigger for a headache attack in subjects data with previous reports in literature in which post- with migraine or inter-ictal TTH [36, 38, 39]. However, IH prevalence ranges from 12 % to 52 % [5, 7, 10–14, further studies are required to clarify the mechanisms 16, 18, 20, 21, 29, 30]. Several variables need to be underlying the two conditions. Mainieri et al. The Journal of Headache and Pain (2015) 16:72 Page 9 of 10

Conclusion impact of headache in Europe: principal results of the Eurolight project. Half of our patients with epilepsy presented either inter- J Headache Pain 21:15–31 4. Dalla Volta G, Di Monda V, Bariselli M, Vignolo LA (1992) Headache and ictal or peri-ictal headaches or both, confirming the bi- epilepsy: a case report of the unusual association of cluster headache and directional relationship between these two pathologies. epilepsy. Ital J Neurol Sci 13(8):699 Migraine is the most prevalent type of headache. Pa- 5. Schon F, Blau JN (1987) Post-epileptic headache and migraine. J Neurol Neurosurg Psychiatry 50(9):1148–1152 tients presenting migraine or tension-type inter-IH seem 6. Ottman R, Lipton RB (1994) Comorbidity of migraine and epilepsy. to be more readily predisposed to develop a seizure- Neurology 44(11):2105–2110 related headache with features similar to their habitual 7. Ito M, Schachter SC (1996) Frequency and characteristics of interictal headaches in patients with epilepsy. J Epilepsy 9:83–86 headache attacks. However, only patients with inter-ictal 8. Ito M, Nakamura H, Honma H, Takeda Y, Kobayashi R, Miyamoto T, Koyama migraine appear to be very prone to present a migraine T (1999) A comparison of post-ictal headache between patients with headache before seizures. Further population studies are occipital lobe epilepsy and temporal lobe epilepsy. Seizure 8:343–346 9. Velioglu SK, Ozmenoglu M (1999) Migraine-related seizures in an epileptic required to establish whether comorbidity exists between population. Cephalalgia 19:797–801 epilepsy and migraine, or whether it is a chance associ- 10. Leniger T, Isbruch K, von den Driesch S, Diener HC, Hufnagel A (2001) ation between two relatively common neurological disor- Seizure-associated headache in epilepsy. Epilepsia 42(9):1176–1179 ders. In addition, prospective studies including the 11. Karaali-Savrun F, Goksan B, Yeni SN, Ertan S, Uzun N (2002) Seizure-related headache in patients with epilepsy. Seizure 11(1):67–69 compilation of a headache and seizure diary may serve 12. Forderreuther S, Henkel A, Noachtar S, Straube A (2002) Headache to establish if one disease represents a risk factor for the associated with epileptic seizures: epidemiology and clinical characteristics. – other. It is crucial to explore this association and identify Headache 42(7):649 655 13. Ito M, Adachi N, Nakamura F, Koyama T, Okamura T, Kato M, Kanemoto K, clinical subgroups in both epilepsy and headache pa- Nakano T, Matsuura M, Hara S (2004) Characteristics of postictal headache in tients sharing common pathogenic pathways and pos- patients with partial epilepsy. Cephalalgia 24(1):23–28 sibly common therapeutic targets. 14. Syvertsen M, Helde G, Stovner LJ, Brodtkorb E (2007) Headaches add to the burden of epilepsy. J Headache Pain 8(4):224–230 Abbreviations 15. Kwan P, Man CB, Leung H, Yu E, Wong KS (2008) Headache in patients with – Inter-IH: Inter-ictal Headache; Peri-IH: Peri-ictal Headache; epilepsy: a prospective incidence study. Epilepsia 49(6):1099 1102 ICHD-2: International Classification of Headache Disorders; TTH: Tension-type 16. HELP Study Group (2010) Multi-center study on migraine and seizure- – Headache; Pre-IH: Pre-ictal Headache; Post-IH: Post-ictal Headache; related headache in patients with epilepsy. Yonsei Med J 51(2):219 224 ILAE: International League Against Epilepsy; AED: Anti-epileptic Drug; 17. Tonini MC, Giordano L, Atzeni L, Bogliun G, Perri G, Saracco MG, Tombini M, CSD: Cortical Spreading Depression; OR: Odd Ratio. Torelli P, Turazzini M, Vernieri F, Aguggia M, Bussone G, Beghi E, EPICEF Group (2012) Primary headache and epilepsy: a multicenter cross-sectional – Competing interests study. Epilepsy Behav 23(3):342 347 The authors declare that they have no competing interests. 18. Duchaczek B, Ghaeni L, Matzen J, Holtkamp M (2013) Interictal and periictal headache in patients with epilepsy. Eur J Neurol 20(10):1360–1366 Author’s contribution 19. Winawer MR, Connors R, Investigators EPGP (2013) Evidence for a shared – FB and SC conceived the study and helped to draft the manuscript. PT, PC, genetic susceptibility to migraine and epilepsy. Epilepsia 54(2):288 295 GM, GG, LZ, CL, MB, LF, MS, AP and PA took part in the design of the study. 20. Gameleira FT, Ataíde L Jr, Raposo MC (2013) Relations between epileptic – GM, CL and LF collected data. GG performed the statistical analysis. GM and seizures and headaches. Seizure 22(8):622 626 LZ participated in writing the manuscript. All authors agreed to accept equal 21. Wang XQ, Lang SY, He MW, Zhang X, Zhu F, Dai W, Shi XB, Wan M, Ma YF, responsibility for the accuracy of the content of the paper. All authors read Chen YN, Yu SY (2014) High prevalence of headaches in patients with and approved the final version of the manuscript. epilepsy. J Headache Pain 15:70 22. Cianchetti C, Pruna D, Ledda M (2013) Epileptic seizures and headache/ Ackowledgements migraine: a review of types of association and terminology. Seizure We thank Anne Collins for editing the English text; Annalia Cesare for 22(9):679–685 secretarial help in keeping in contact with patients and controls; Elena Zoni 23. Headache Classification Subcommittee of the International Headache for help in manuscript editing; and the EEG technicians of our department Society (2004) The International Classification of Headache Disorders: 2nd for recording the patients. This work was not supported by any grant. edition. Cephalalgia 24(Suppl 1):9–160 24. 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